Building Better Drugs, in Five Steps or Less

When the drug ezetimibe was approved in 2002, it was hailed by its makers as a new tool for lowering cholesterol and fighting heart disease in patients. In clinical trials, the drug (marketed by Merck as Zetia) lowered levels of low-density lipoprotein or LDL, the so-called “bad cholesterol” associated with atherosclerosis, the thickening of blood vessels that can lead to stroke and heart attacks. Though LDL was also the target of the highly successful statin drugs, Zetia passed the FDA because it offered an alternative mechanism for reducing cholesterol levels, and soon was making billions of dollars a year for the pharmaceutical company. But as more and more people took the drug and more research was conducted, the scientific data did not match the marketing hype, with large clinical trials failing to find a protective effect against cardiac events and even finding in some cases that it made blood vessels thicker.

Sadly, the story of Zetia is not that unusual. In recent years, other drugs such as Vioxx and Redux have been come under fire when dangerous side effects or underwhelming clinical results became apparent after approval. These high-profile failures (and the inevitable ensuing lawsuits) have threatened to slow drug development, as pharmaceutical companies are understandably nervous about investing big money in a potential dud. Expensive new drugs that offer little to no improvement over pre-existing treatments also cause damage, by needlessly raising health care costs. So what changes can we make to the U.S. health care system to promote the creation of innovative new drugs worth their price tag?

Three authors, including G. Caleb Alexander of the University of Chicago Medical Center, proposed five not-so-easy fixes in a recent issue of Annals of Internal Medicine. Their strategy includes reforms of the FDA’s drug approval process, drug labels, and the payment strategy of insurance companies on the other. For drug companies that may not like the extra squeeze, incentives can be built into the system to sweeten the deal for developing more effective treatments and drugs for currently untreatable diseases. “Despite these challenges, the United States has a long history of successfully improving the safety and value of prescription drugs, and substantial progress can still be made,” the authors write.

1. Raise the Bar

One way to prevent surprises when new drugs are transferred from clinical trials to the real world is to require that higher standards are met before approval. Instead of just demonstrating the drug’s superiority to a placebo treatment, researchers could be required to prove that the new drug is better than the current standard of care. Clinical trials should also be designed to measure effects on clinical outcomes, such as atherosclerosis, rather than physiological measures, such as LDL.

2. Semi-Approval

For an FDA approval process that some already criticize as to slow, these additional requirements could further gum up the works. To allow time for this more thorough review, the authors suggest a more nuanced FDA approval, adding a new “conditional” approval stage where the drug could be available with strings attached. For instance, direct-to-consumer advertising could be restricted while more data is collected on the drug’s effects in a larger, more diverse population.

3. The Patent Carrot for the Regulatory Stick

For the pharmaceutical companies, all of the above is a nightmare that would extend the cost and time it takes to bring a new drug to market. As an olive branch, the paper suggests extending the patent exclusivity for new drugs that meet these most stringent standards, giving the pharmaceutical company more time to collect profits before generics are allowed to reach the market. One suggestion is to start the patent clock when the drug is approved, so that the FDA process does not eat up valuable months and years of exclusivity for the drug’s developer. Such a measure would also ease up the pressure on the regulators, reducing “the tension between the ticking clock of patent protection and drug safety,” the authors write.

4. Better Labels, Educated Patients

Every so often, a new effort is made to create clearer, more informative drug labels, and the result is the fold-out poster with microscopic text included with every pill bottle. Alexander and colleagues write that drug labels should follow the lead of food labeling, providing practical information to consumers in a standardized and easily-understood manner. Informed consumers can make better decisions about drug choice, such as in cases where a cheap generic is equally effective as a pricey brand name drug. But as the authors admit, condensing the complex results of clinical trials “is an onerous task.”

5. Insurance Rewards…where Appropriate

If consumers can’t be counted on to weigh the effectiveness of one drug versus another, perhaps their insurance companies can take on the greater responsibility. One would think that health insurance providers would already be highly motivated to only provide reimbursement for drugs proven to be effective and worth their price, but inefficiencies still occur – the paper cites $2.8 billion spent in 2009 on esomeprazole, a drug for stomach conditions “with no clear clinical advantages” over an alternative, nearly identical medication. Tiered payment models which base reimbursement rates on scientific evidence may be a further incentive for pharmaceutical companies to meet the higher standards proposed above.

For many of these reforms, federal legislation would be required to pass a deeply divided Congress. But the history of pharmaceutical regulation in the United States offers cause for optimism, the authors write, from the 1906 Pure Food and Drugs Act (which created the modern FDA) to a set of amendments in 1962 that established strict standards of evidence. As current FDA Commissioner Margaret Hamburg said in a lecture last year, “the increasingly rigorous standards of the FDA created the conditions for innovation and progress in the pharmaceutical market, and together, American medicine and the FDA have accomplished an enormous amount. Now our challenge is to continue to move forward.”